CZ293945B6 - Medicament useful in treating amyotrophic lateral sclerosis - Google Patents

Abstract

In the present invention, there is disclosed the use of sulfamate compounds of the general formula I, in which X represents CHi2 or oxygen; Ri1 represents hydrogen or alkyl containing 1 to 4 carbon atoms and Ri2, Ri3, Ri4, Ri5 represent independently on each other hydrogen, alkyl containing 1 to 3 carbon atoms, whereby when X is CHi2, Ri4 and Ri5 can denote alkene groups joined to form a benzene ring and, when X is oxygen, Ri2 and Ri3 and/or Ri4 and Ri5 together may be a methylenedioxy group of the general formula II, in which Ri6 and Ri7 are the same or different and are hydrogen, alkyl having 1 to 3 carbon atoms or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring; in particular topiramate, for the preparation of a medicament intended for treating amyotrophic lateral sclerosis (ALS).

Description

The invention relates to a medicament for the treatment of amyotrophic lateral sclerosis.

BACKGROUND OF THE INVENTION

Compounds of formula I

(I) are structurally novel compounds with antiepileptic effects which have highly anticonvulsant effects in animal experiments (Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, J. Med. Chem. 30, 880-887, 1987; Maryanoff BE, Costanzo MJ, Shank RP, Schupsky JJ, Ortegon ME, and Vaught JL, Bioorganic & Medicinal Chemistry Letters 3, 2653-2656, 1993, McComsey DF and Maryanoff BE, J. Org. Chem, 1955). These compounds are disclosed in U.S. Pat. No. 4,513,006. One of these compounds 2,3: 4,5-bis-O- (1-methylethylidene) -β-Dructopyranose amidosulfate is known as topiramate, which has been shown to be effective in clinical trials. adjuvant therapy for human epilepsy, or monotherapy for the treatment of single or complex seizures and secondary generalized seizures (Faught E, Wilder BJ, Ramsay RE, Reife RA, Kramer LD, Pledger GW, Karim RM et al, Enilepsia 36 (S4) 33 1995; Sachdeo SK, Sachdeo RC, Reife RA, Lim P. and Pledger G, Epilepsia 36 (S4) 33, 1995), and is in common distribution for the treatment of single or complex partial epileptic seizures with or without secondary generalized seizures, in Applications to the UK, Finland, the United States and Sweden, and many countries around the world, are submitted for approval by its regulatory authorities.

In the first studies, compounds of Formula I were found to exhibit anticonvulsant activity in the classical maximum electroshock seizure (MES) test in mice (Shank RP, Gardocki JF, Vaught JL, Davis CB, Schupsky JJ, Raffa RB, Dodgson SJ, Nortey SO, Maryanoff BE, Epilepsy 35, 450-460, 1994). Subsequent studies have found that the compounds of Formula I are also highly active in the rat MES test. In recent years, topiramate has been found to effectively reduce seizures in several models of rodent epilepsy (Nakamura J, Tamura S, Kanda T, Ishii A, Ishihara K, Serikava T, Yamada J, and Sasa M, Eur. J. Pharmacol, 254 8389, 1994), and in a model of induced epilepsy (Wauquier A. and Zhou S, Epilepsy Res, 24, 73-77, 1966)).

In recent preclinical studies with topiramate, undetected pharmacological properties have been found, suggesting that topiramate should be effective in the treatment of some other neurological diseases. One of them is amyotrophic lateral sclerosis (ALS).

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SUMMARY OF THE INVENTION

It is an object of the invention to use sulfamate compounds of the formula I

CH ₂ OSO ₂ hlHRi

R4 (i) wherein

X represents CH ₂ or oxygen;

R 1 is hydrogen or C 1 -C 4 alkyl; and

R ₂ , R ₃ , R 1, R ₅ are each independently hydrogen or C 1 -C 3 alkyl, wherein when X is CH ₂ , R 4 and R ₅ can represent alkene groups which are joined together to form a benzene ring and when X is an oxygen atom, R ₂ and R ₃ and / or R 4 and R ₅ may together represent a methylenedioxy group of formula II wherein:

R 5 and R ₇ are the same or different and each represents a hydrogen atom or a C 1 -C 3 alkyl group or R ₇ and R ₇ represent alkyl groups which are joined together to form a cyclopentyl or cyclohexyl ring;

for the manufacture of a medicament for the treatment of amyotrophic lateral sclerosis.

R 1 is in particular hydrogen or C 1 -C 4 alkyl, such as methyl, ethyl and isopropyl. An alkyl group in this specification includes a straight and branched chain alkyl. The alkyl groups in the substituents R ₂ , R ₃ , R 4, R ₅ , R ₁ and R e have about 1 to 3 carbon atoms and include methyl, ethyl, isopropyl and propyl.

A particular group of compounds of formula I is that in which X is oxygen and both R ₂ and R _3, and R 4 and R ₅ together are methylenedioxy groups of the formula II, wherein Re and _R7 are both hydrogen, both alkyl, or combine to the formation of a spiro-cyclopentyl or cyclohexyl ring, especially when R e and R ₇ both denote alkyl groups such as methyl groups. A second group of compounds are compounds wherein X is CH ₂ and R4 and _R are joined to form a benzene ring. A third group of compounds of formula I are compounds in which R ₂ and R ₃ are hydrogen.

The compounds of formula I can be prepared by the following methods.

(a) Reaction of an alcohol of formula RCH ₂ OH with a chlorosulfate of formula C ₁ SO ₂ NH ₂ or C ₁ SO ₂ NHR 1, in the presence of a base such as potassium α-butoxide or sodium hydride, at a temperature of about

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-20 ° C to +25 ° C and in a solvent such as toluene, THF or dimethylformamide, wherein R is a group of the following formula III:

(III) (b) Reaction of an alcohol of formula RCH 2 OH with a sulfuryl chloride of formula SO 2 Cl 2 in the presence of a base such as triethylamine or pyridine at a temperature of -40 ° C to 25 ° C in a solvent such as diethyl ether or methylene chloride to form the chlorosulfate of formula RCH2OSO2Cl.

Chlorosulfate of formula RCH ₂ OSO ₂ C1 can then be reacted with an amine of formula R ₁ NH ₂ at a temperature of about 40 ° C to 25 ° C in a solvent such as methylene chloride or acetonitrile to form a compound of formula I. The reaction conditions for process (b) are also described Tsuchiya T. et al., Tet. Letters, No. 36, pp. 3365-3368 (1978).

(c) Reaction of RCH ₂ OSO ₂ Cl chlorosulfate with a metal azide such as sodium azide in a solvent such as emthylene chloride or acetonitrile to form the azido sulfate of RCH ₂ OSO ₂ N ₃ as described by Hedaytullah M., Tet. Lett., Pp. 2455-2458 (1975). This azidosulfate is then reduced to a compound of formula I in which R 1 is hydrogen by catalytic hydrogenation using, for example, a noble metal and H ₂ or by heating with metallic copper in a solvent such as methanol.

The starting components of the formula RCH ₂ OH can be obtained by a commercial method or by methods known in the art. For example, the starting components of formula RCH ₂ OH, where both R ₂ and R ₃ , and R 4 and R ₅ have the same meaning according to formula II, can be obtained as described by Brady RF, Carbohydrate Research, Vol. 14, pp. 35-40 (1970), or by reacting ketone trimethylsilylenol ether or aldehyde R? CORv with fructose at about 25 ° C in a solvent such as a halohydrocarbon such as methylene chloride in the presence of a protic acid such as hydrochloric acid or a Lewis acid such as is zinc chloride. The reaction with trimethylsilylenol ether is described in Larson GL et al., J. Org. Chem., Vol. 38, No. 22, p. 3935 (1973).

Further, carboxylic acids and aldehydes of formula RCOOH and RCHO can be reduced to compounds of formula RCH ₂ OH by standard reduction methods, for example by reaction with lithium aluminum hydride, sodium hydrogen borate or borane-THF complex in an inert organic solvent such as diglyme, THF or toluene. 0 ° C to 100 ° C as described, for example, in House HO, "Modern Synthetic Reactions", 2nd Edition, pp. 45-144 (1972).

Compounds of formula I may also be prepared as disclosed in U.S. Patent 4,513,006, which is incorporated herein by reference.

The compounds of formula I include the various individual isomeiy well as the racemates thereof, e.g., the various alpha and beta attachments, i.e. the position of the substituents R _2, R _3, R 4, and _R above or below the plane of the drawing at the 6-membered ring. Preferably, the oxygen atoms of the methylenedioxy group II are attached to the same side of the 6-membered ring.

DETAILED DESCRIPTION OF THE INVENTION

The activity of the compounds of formula I in the treatment of amyotrophic lateral sclerosis was determined based on studies indicating that topiramate exerts an antagonistic effect on the AMPA / kainate glutamate receptor subtype (The RW Johnson Pharmaceutical Research Institute, Intemational Research Report, Document ID Accession No. A500,960; JW) Gibbs III, S. Sombati, RJ Delorenzo and DA Coulter, Epilepsia37, in press, 1996), and on the basis that ALS is a chronic neurodegenerative disease in which glutamate regulation is impaired (JD Rothstein, M. Van Kammen, AI Levey, LJ Martin and RW Kunci, Annals Neurology 38, 73-84). Glutamate is used in NS as the main excitatory neurotransmitter. This function is mediated by a physiological process in which glutamate molecules are deposited in vesicles at the synaptic nerve endings. These molecules are released into the synaptic cleft by depolarizing the synaptic membrane with an action potential, then activating specific receptors in the postsynaptic membrane of the target neurons. Then these molecules are removed from the synaptic cleft for the 15 thein "transporters" in the synaptic terminal membrane of the presynaptock neuron and in the glial cells (astrocytes). In ALS, the activity of these transport proteins appears to be abnormally low, which may cause an abnormal increase in glutamate concentration in the synaptic cleft. This, in turn, may cause excessive activation of glutamate receptors, which, if high enough, may cause nerve cell death (JD Rothstein, Pathogenesis and Therapy of Amyotrophic 20 Lateral Sclerosis, edited by G. Serratrice and T. Munsat, Advances in Neurology, 68, 7-20, LippocottRaven Publishers, Philadelphia, 1995).

Studies have found that topiramate antagonizes the activity of neurons induced by kainate, a glutamate analogue, that selectively activates certain glutamate receptor subtypes (JW Gibbs III, 25 S. Sombati, JR Delorenzo, and DA Coulter, Epilepsia37, in the press, 1996; The RW Johnson Pharmaceutical Research Institute, Intemational Research Reports, Document ID Accession Numbers A500,960 and 398533: 1). In these studies, primary cultures enriched in neurons derived from fetal ratshipampamp were grown in vitro for 14 to 21 days under conditions allowing high density and development of many synaptic contacts. Patch-clamp procedures with whole perforated cells are used to study the electrical properties of neuronal membranes. In this method, electrical contact between the indicating electrode and the intracellular fluid is achieved using amphotericin B to form pores in the cell membrane. This allows accurate measurement of the potential on the membrane or the passage of current through the membrane. The kainate, topiramate, and other test compounds are applied to the neurons by microfiltration using a 35 Teflon concentration-controlled multi-dose pipette. Topiramate (dissolved in DMSO at 1 M concentration is then diluted with neuronal incubation medium) is applied at concentrations of 0.01, 0.1, 1.10 or 100, and the kainate is applied at concentrations of 0.1 or 1 mM.

In an initial series of experiments, the antagonistic effect of topiramate on kainate-induced currents 40 was determined based on membrane potential. In experiments in which kainate-induced membrane currents were recorded at terminal voltages of -60 mV to +60 mV and at 20 mV increments, it was found that the amount of antagonist effect decreased with membrane depolarization. Therefore, the efficacy of topiramate on membrane potentials was highest near the resting state.

The time course of topiramate antagonistic effect was evaluated in the second series of experiments. Kainate pulses were performed in the medium for 3 seconds at 1 minute intervals, and once baseline levels of kainate-induced currents had stabilized, topiramate was applied in a constant manner over a period of several minutes to 20 minutes. Within one minute after topiramate 50 administration, a partial blockage of the kainate-induced current was evident, but at saturation concentrations, the kainate-induced current was only reduced by 20 to 40%. This effect can be easily reversed by removing topiramate (washing it out) within 5 minutes. However, with constant application of topiramate for more than 10 minutes, the antagonist effect on kainate-induced cell membrane currents increases significantly, and kainate 55-induced currents remain suppressed when topiramate is removed. Curves were found for both phases of topiramate blocking action

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I concentration-response. The concentration for each phase corresponding to an EC ₅₀ value is about 1 micromolar. However, the concentration required for maximum response for the first phase is about 0.1 mM (I phase block) but only about 0.010 mM for the second phase (II phase block).

Given convincing evidence that the functional state of glutamate receptors is partially regulated by protein kinases and phosphatases (LY Wang, FA Taverna, XP Huang, JF MacDonald, and D. R. Hampson, Science, 259, 1173-1175, 1993), phase II blocking may be by the dephosphorylation of kainate-activated receptors. Based on evidence that cAMP-dependent protein kinase (PKA) modulates kainate-activated receptors (LY Wang, FA Taverna, XP Huang, JF MacDonald, and DR Hampson, Science 259, 1173-1175, 1993), a series of experiments were performed to determine dibutyrylcyclic here. AMP could restore kainate excitatory activity following topiramate-induced phase II block; ie to cause the "irreversible" effect to be reversible. These experiments clarified that dibutyrylcyclic AMP partially or completely restored the kainate-induced current. In another series of experiments, a non-specific phosphatase inhibitor, okadaic acid, was administered at 1 micromolar concentration before and during topiramate administration to determine whether inhibition of kainate-activated receptor dephosphorylation could prevent the phase II blocking effect of topiramate. Okadaic acid has little effect on the kainate-induced current prior to topiramate administration, and does not affect the primary antagonistic effect of topiramate (block I phase); however, as expected, phase II of the block was prevented. These results show that topiramate directly or indirectly inhibits the ability of protein kinase (PKA) to phosphorylate kainate-inactivated receptors, which over time become receptors in a dephosphorylated state in which they are not sensitizable (cannot be activated).

Regardless of the mechanism by which topiramate antagonizes the effect of kainate on glutamate receptors, this antagonistic effect will limit the degree of receptor activation. In pathological situations in which glutamate receptor over-activation, such as occurs in ALS, occurs, drug-induced reduction in glutamate receptor activation will also reduce the number of extinct nerve cells.

For the treatment of amyotrophic lateral sclerosis (ALS), the compound of formula I may be administered at a daily dose in the range of about 100 to 800 mg, usually given to an average adult in two divided doses. A unit dose contains about 25 to 200 mg of active ingredient.

In preparing the pharmaceutical compositions of the invention, one or more amidosulfate compounds of formula I are intimately mixed with the pharmaceutical carrier by conventional pharmaceutical mixing methods, wherein the carrier may be of a different nature depending on the dosage form required for administration. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. For liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavor enhancers, preservatives, colorants and the like; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, glidants, binders, disintegrants and the like. For ease of administration, oral and unit dosage forms are preferably tablets and capsules, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by conventional means. Suppositories are prepared using cocoa butter as carrier. For parenteral formulations, the carrier is usually sterile water, although these formulations may also contain other ingredients, for example, solubilizers or preservatives. Injectable suspensions may also be prepared using suitable liquid carriers, suspending agents and the like. Typically, topiramate for oral administration is available in round tablets containing 25 mg, 100 mg or 200 mg of active ingredient. The tablet contains the following excipients: lactose hydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, kamauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.

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These pharmaceutical preparations contain in a dosage unit, for example, a tablet, a capsule, a powder for injection, a teaspoon, a suppository and the like from about 50 to about 200 mg of the active ingredient.

Claims (2)

1. Use of sulfamate compounds of formula I wherein X represents CH ₂ or oxygen; R 1 is hydrogen or C 1 -C 4 alkyl; and R 2, R ₃ , R ₄ , R 5 are each independently hydrogen or C 1 -C 3 alkyl, wherein when X is CH ₂ , R 4 and R ₅ may represent alkene groups which are joined together to form a benzene ring and when X is oxygen, R ₂ and R 3 and / or R 4 and R ₅ may together represent a methylenedioxy group of formula (II), R? where R ₆ and R ₇ are the same or different and each represents a hydrogen atom or a C 1 -C 3 alkyl group or R 6 and R ₇ are alkyl groups which are joined together to form a cyclopentyl or cyclohexyl ring; for the manufacture of a medicament for the treatment of amyotrophic lateral sclerosis. Use according to claim 1, wherein the sulfamate compound of formula I is topiramate.